The epidermal growth factor receptor (EGFR) is composed of an extracellular ligand-binding domain, a transmembrane segment and an intracellular tyrosine kinase domain. Upon the binding of a ligand such as epidermal growth factor (EGF) and transforming growth factor α (TGFα), the EGFR forms homo or heterodimers with the other members of the ErbB family resulting in autophosphorylation of the intracellular domain and activation of the downstream signaling pathways, including Ras-induced MAP kinase pathway, the PI3-kinase pathway and the JAK/STAT pathway. This can signal cancer cell proliferation, inhibition of apoptosis, and activation of invasion and stimulate tumor-induced neovascularization. Human cancers expressing EGFR are often treated with an EGFR-specific antibody that inhibits receptor signaling and tumor cell proliferation, such as the approved anti-EGFR mAb, cetuximab (Erbitux®).
The direct mechanism of action of cetuximab is the blockade of ligand-receptor binding and thereby inhibition of ligand-mediated activation of the EGFR tyrosine kinase. As a result of this EGFR blockade, a variety of processes regulated by the EGFR-signaling pathways in tumor cells or stromal cells in the tumor microenvironment are disrupted (Fan Z, et al. 1994; Abanell J, et al. 2001; Prewett M, et al. 1996; Huang S M, et al. 1999; Fan Z, et al. 1993a; Fan Z, et al. 1993b). Other mechanisms including antibody-dependent cellular cytotoxicity (ADCC) and receptor internalization are likely to play an important role as well (Kawaguchi Y, et al. 1996; Kimura H, et al. 2007). ADCC is dependent on interactions between the cellular FcγR and the monoclonal antibody, which triggers innate immunologic responses involving natural killer cells, monocytes, macrophages, activated T-lymphocytes and granulocytes. Receptor internalization down regulates the number of available cell surface receptors and could therefore affect EGFR activation.
Hypersensitivity reactions are a frequent side effect of cetuximab, and can prove fatal for recipients. The present disclosure provides alternative EGFR-targeted therapies useful for individuals having sensitivities to cetuximab that preclude its further use. In particular, the disclosure provides an anti-EGFR antibody having the same specificity and efficacy as cetuximab, but having modifications that render it less immunoreactive and more stable than cetuximab. The antibody is useful alone or in combination with one or more additional therapeutic agents for the treatment of EGFR-expressing cancers.